Injection Of Solutions
By far the most widely used method for parenteral injection of drugs is by injection of an aqueous solution using a hypodermic syringe. The use of aqueous solutions is associated with a number of inherent problems. In order to inject a given volume of drug, a much larger volume of water and different additives also have to be injected. Weight ratios of drug to solvent may be in the range of 1:100 to 1:1,000. For intramuscular injection, the pain associated with injection is primarily caused by the volume injected, not by the penetration of the skin. Any reduction in volume would thus lead to a reduction in pain for the patient.
For some drugs, the solubility in water is very low. This has two consequences. Either the solutions become dilute and thereby the injection volume increases. Or, additives such as surfactants must be added to the solution to increase the concentration of active ingredient. Such additives or surfactants are potentially toxic. The potential for toxicity greatly limits the possibilities for developing formulations, thus potentially limiting the availability of important drugs.
Generally, an aqueous solution of any given drug is chemically less stable than a dry formulation of the same drug. Furthermore, an aqueous solution is prone to microbial contamination and needs to be sterilised by use of heat, radiation, filtration or chemical means. To increase the shelf life of aqueous drug formulations preservatives, stabilisers, anti-oxidants, biocides etc are often added. These additives may also add to the toxicity of the formulation. Alternatively or additionally, the aqueous solutions may require special storage conditions at low temperature to avoid chemical or microbial break down of the active ingredients and to avoid microbial growth.
For parenteral injection, the syringe needs to penetrate the epidermis or the mucosa. Whereas the tip of the syringe may be pointed and very thin, the presence of a hole provides it with a cutting edge which produces a micro-wound in the epidermis and thereby pain. Furthermore, for many patients, especially children, the pre-injection fear for pain is a factor to consider.
A considerable risk for hospital professionals as well as for sanitation workers is the risk of contamination from used hypodermic needles, which may carry infection. Patients may also be infected through multiple uses of needles.
Solid Dose Administration
Powder Injection
A number of publications deals with the task of injecting drugs formulated as solid microparticles. WO 94/24263 (Oxford Biosciences Ltd) discloses an apparatus for parenteral injection of particles or powders of a therapeutic agent. The therapeutic agent may be pure or mixed with a carrier, which will typically constitute less than 75%, preferentially less than 50% of the composition. Particles ranging from 0.1 to 250 μm in diameter are injected by means of a pressurised gas such as helium.
WO 96/03978 (Quadrant Holdings Cambridge Ltd) discloses a drug formulation in the shape of micro-fibres or micro-needles 1 to 150 μm in diameter and 5 to 150 μm long. The drug formulation may contain up to 20% active substance dispersed in an amorphous glassy matrix made from carbohydrate or carbohydrate derivatives. The preferred way of administering the formulation is through ballistic injection.
Due to the variation in particle size and shape, it is difficult to obtain a very precise penetration depth by powder injection. In parenteral injection, it is imperative to deliver the drug to the correct tissue, since drugs which do not penetrate the cutis are not taken up by the body, and since some drugs should reach the muscular tissue, some the subcutis and some the cutis to be transferred to the blood stream within a predetermined time limit. Energising means used for injecting the particles may include compressed gas, and explosives such as, propane, gasoline, or gunpowder. Such explosive means provides the apparatus for their administration with potential danger.
Implants
Solid dose drug formulations may also be administered by implantation. WO 93/10758 (Pitman Moore Inc) discloses such a sustained release formulation comprising an amorphous carbohydrate glass matrix, a biologically active therapeutic agent, and a hydrophobic substance which modifies the rate of release of the therapeutic agent from the glass matrix. This formulation may be in the shape of a rod extruded through a syringe and cut to lengths of 5 mm. These formulations comprise from 2 to 20% therapeutic agent. The carbohydrate glass matrix makes up between 60 and 90% of the formulation and is made from a mixture of one carbohydrate, a recrystallisation retarding agent and water. The formulations are intended for implantation but may also be administered orally.
WO 96/03978 (Quadrant Holdings Cambridge Ltd) (op.cit.) also encompasses macroscopic beads for subdermal implantation.
Whereas implants are excellent for sustained release they are not suitable for drugs, which have to be administered frequently, such as insulin or growth factors, or at varying time intervals, due to the need for medical assistance for their administration.
Needle Injection Systems
A few publications also deal with the task of administering a solid pharmaceutical composition having the shape of a needle or toothpick. Such formulations can be administered with greater precision than the abovementioned powders.
WO 96/08289 (Societe de conseils de recherches et d′application scientifiques S.A) discloses a device for parenteral administration of a medicament. The medicament has the shape of one end of a toothpick. Its dimensions range from 1 mm to 3 cm in length. The diameter may be up to 2 mm. The medicament comprises at least 50% active ingredient but may consist of 100% active ingredient without any carrier. Suitable water soluble carriers are e.g. hyaluronic acid, cellulose, polyalcohols, sugars, geletin, polyvinylpyrrolidone and starches. The carrier may also be water insoluble but biodegradable to provide sustained delivery. The medicament has a crush strength of 8 millipoise and is prepared using conventional techniques such as compression, thermofusion, or extrusion.
Macroneedles for injection are also disclosed in WO 96/03978 (Quadrant Holdings Cambridge Ltd). These needles are of the dimension 0.1 to 4 mm in diameter and 1 to 30 mm in length. The needles comprise a glassy vehicle and an effective amount of at least one guest substance. The glassy vehicle may comprise either a stabilising polyol or a hydrophobic carbohydrate derivative. The amount of guest substance may be up to 20% of the composition. The composition is disclosed as having sufficient compressive strength to be driven directly through the skin.
To obtain a satisfactory solid-dose-parenteral-injection, the composition to be injected must be of small volume to avoid injection pain and to achieve rapid dissolution. The small volume should be obtained by providing the composition with a strong carrier, whereby the amount of drug can be increased. The composition should be provided with a well-defined strength to make it possible to penetrate the cutis of the patient, be it an animal or human being. Furthermore, the composition should be long-term stable at ambient temperature in terms of both strength and structure of the composition and the biological activity of the drug. The carrier used to provide the necessary strength should comprise compounds that are tissue compatible and that are contained in the pharmacopoeia.